JPS6289649A - Antispasmodic and medicine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] This invention relates to anticonvulsant drugs and methods of using these drugs, where these drugs include 3-
and 4-amino-N-(alkylphenyl)benzamide compounds. Among these benzamide compounds, the most preferred for this use are:
4-amino-N-(2,6-dimethylphenyl)benzamide.

BACKGROUND ART Today, only 50-75% of epilepsy patients are able to obtain significant relief from their spasticity with the several anticonvulsant drugs on the market in the United States. In addition, due to their therapeutic effects, sedation, ataxia, psychotic symptoms, depression with the risk of suicide, gastrointestinal disorders, gingival hyperplasia, lymphadenoma, upper blast cell anemia, liver damage, renal damage, and hirsutism may occur. , and may cause serious side effects such as fetal malformations. These side effects range in severity from mild sedation to death from aplastic anemia, but most importantly, most commercially available anticonvulsants have very low therapeutic indices. That's what it means. For example, phenytoin, one of the most widely used anticonvulsants, is capable of suppressing convulsions in humans only when plasma white concentrations reach 10 μg. Side effects such as nystagmus appear at about 20μ9,
Ataxia appears at 30μ9. Also, lethargy clearly occurs at about 40μ9. Regarding these issues, see [The Pharmacological Basis of Therapeutics J]
The pharmacological B
a5is of Therapeutics), (
Gilman, Gutsudman, and Gutsdman, eds., 6th ed.
Matsukumilan Publishing Co., New York (19
1980), p. 455]. These facts have led many epilepsy psychiatrists to express a clear need for more selective and less toxic anticonvulsants.

The use of certain aminobenzamide compounds as anticonvulsants has been reported in U.S. Pat. No. 4,379,165 (1983).
), and the Journal of Medicinal Chemistry (J, Medicinal C
hemistry) Vol. 27, pp. 779-782 (198
4). These compounds include the previously used phenobarbital, phenytoin,
Although they have shown useful levels of anticonvulsant activity compared to basic anticonvulsant drugs such as mephenytoin and carbamazepine, achieving such levels of anticonvulsant activity requires that these agents be combined with the desired activity. It is necessary to use relatively large amounts to obtain a level of control, and the risk of undesirable side effects is therefore also increased. Also, the aminobenzamide compounds described in these two publications are structurally limited in scope. For example, in the benzamide moiety of those compounds, the phenyl or benzyl group does not contain any nuclear substituents other than the amino group.

Grandma Tikakis contains, among other compounds, 4-amino-N-(2-methylphenyl)benzamide, 4-amino-N-(4-methylphenyl)benzamide and 4-amino-N-(2-methylphenyl)benzamide.
-Amino-! Disclosed 1-(2,6-dimethylphenyl)benzamide along with its production method
Compt, Rend, ) Volume 259 (23), 42
95 (1965), and Chemical Abstracts 62, 11732b (1965)]. These publications are silent regarding the usefulness of these compounds.

Certain selected 4-aminobenzoic acid anilides are disclosed for their preparation and use as analgesics, anti-inflammatory agents, antipyretics or anti-inflammatory agents [Chem, Abs.

) Volume 75, 35466g (1971), and Chemical Abstracts (Chem, Abs, ) Volume 76, 140260d (1972).

Phenytoin and calmazepine were administered approximately 8.81-9.501/kg (MES) by intraperitoneal administration (mice).
ED5°) (see below and references), but prior to this invention, there had been no anticonvulsant activity that was significantly higher than the level of activity provided by these drugs. No seizure medication was provided.

U.S. Patent No. 4,379,165 and Journal of
Medicinal Chemistry (J, Med.

The aminobenzamide compounds described in Chem.
Figure 3 shows M E S E D 5o activity levels of M.

DISCLOSURE OF THE INVENTION It is an object of the present invention to provide a new class of anticonvulsants, certain 3- and 4-amino(alkylphenyl)benzamides, some of which , exhibits significantly improved levels of anticonvulsant activity compared to previously available anticonvulsants.

It is also an object of the present invention to provide anticonvulsants that can be used relatively safely and at dosages that exhibit useful levels of anticonvulsant activity.

Another object of this invention is to provide an anticonvulsant that can be effectively administered orally.

It is also an object of the present invention to provide a novel class of 3- and 4-
An object of the present invention is to provide amino(alkylphenyl)benzamides.

This invention relates to certain 3- or 4-amino-N-(alkylphenyl) compounds described in detail below in mammals.
Treatment of convulsions in mammals in need of such treatment by administering an effective amount of benzamides, particularly 4-amino-N-(2,6-dimethylphenyl)benzamide, or a pharmaceutically acceptable acid addition salt thereof. Provides methods for treating and preventing.

The present invention also provides for the use of benzamides, particularly 4-amino-N-(2,6-dimethylphenyl)benzamide, or a pharmaceutically acceptable acid addition salt thereof, as an active ingredient, and a pharmaceutically acceptable carrier and diluent. Or provide a pharmaceutical formulation containing the same together with an excipient.

This invention therefore provides compounds (1) 3- or 4-amino-N-[(alkyl)nphenyl]henzamides (]) where the alkyl group of these compounds has from 1 to about 4 carbon atoms. and n is 1 to 2) in an effective amount thereof as a treatment or prophylaxis for convulsions in mammals. Examples of the alkyl group contained in these compounds include methyl, ethyl, propyl, isopropyrol, and butyl. In addition, these compounds have the following formula (II) (wherein R is a C, -C4 argyl group, and 1 to 2
Can you show the structure of (1!'; I is included) as a) °-4'' 3-manoni:J.1-aminobenzamide compound?

Compounds having the structure (II) listed in Table 1 below were made according to the present invention and evaluated as anticonvulsants. We believe that these compounds have never before been provided in the prior art.

, Table 1 Structural formula (Novel compound having Il atoms are not shown again) 1-Structural a The most preferred structure that can be used as a phenylic anticonvulsant on the right side of formula (II) (the compound of D is 4 -amino-N-(2,6-dimedylphenyl)benzamide.

The 3- and 4-aminobenzanilide compounds of this invention can be prepared by methods known in the art. Such a method is similar to the prior art described above, namely Geramachikakis, Comte Rendu i Séances de l'Academie des Sciens (C.

mpt, Rend, ) vol. 259 (23) p. 4295 (1965) and Chemical Abstracts (Ch.
em.

Abst, Vol. 62, 11732b (1965), Vol. 75, 35466g (1971) and Vol. 76, 140260d (1972). , 4-amino-N-(4-methylphenyl)
Methods for making several of the compounds of structure (1) generally described above are described, including benzamide and 4-amino-N-(2,6-dimedylphenyl)benzamide. Structures (1) and (Il) analogs not described can be prepared using similar methods such as the following Reaction Scheme I (R and 1 are as shown).

Reaction formula ■ The benzamide compounds of this invention are the compound itself,
Or it can be used as a medicine in the form of its pharmaceutically effective acid addition salt.

The pharmaceutically acceptable acid addition salts of this invention can be prepared by standard known methods using those acids to render the basic aniline group of the benzamide compounds of this invention sufficiently acidic. Examples of such salts include salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous, etc., and aliphatic monocarboxylic acids and Examples include salts derived from organic acids such as dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids and alkanioic acids, aromatic carboxylic acids, aliphatic and aromatic sulfonic acids, and the like. Specific examples of such pharmaceutically acceptable salts include sulfates, metaphosphates, pyrophosphates, hydrochlorides, hydrobromides, hydroiodides, Hydrogen salt, oxalate, maleate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfonate, methanesulfonate, propane sulfonate, naphthalene-1-
Examples include sulfonate salts and naphthalene-2=sulfonate salts. A particularly preferred salt derived from an inorganic acid is the hydrochloride.

The selected benzamide compounds can be administered orally, rectally, transdermally,
It can be administered as an anticonvulsant by various routes of administration such as subcutaneous, intravenous, intramuscular or intranasal administration. They are usually used in the form of pharmaceutical compositions. The compounds of this invention are characterized by their effectiveness as anticonvulsants, especially by oral administration. The invention encompasses pharmaceutical compositions containing from about I to about 95% (by weight) of a benzamide compound, or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier.

To prepare the pharmaceutical compositions of this invention, the active ingredient is typically mixed with a carrier, diluted with a carrier, or filled into a carrier, which may take the form of a capsule, sachet, paper, or other container. be able to. When the carrier is used as a diluent, it can be in solid, semisolid or liquid form as a base, excipient, or medium with which the active ingredient can be diluted. Thus, the compositions of this invention can be used as tablets, emulsions, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, (in solid or liquid media). )
, ointments [eg containing up to 10% (by weight) of active compound], soft and hard gelatin capsules, suppositories, sterile injectables, and sterile packaged powders.

Suitable carriers and diluents include lactose, dextrose, sucrose, turbitol, mannitol, starch, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, Water, syrup, methyl cellulose, methyl oxybenzoate, propyl oxybenzoate, talc, magnesium stearate, mineral oil, and the like. The formulation also contains lubricants, wetting agents, emulsifiers and! ! Topical preparations, preservatives, sweeteners, flavors, etc. can be added. The compositions of this invention may be formulated to provide rapid or sustained or delayed release of the active ingredient after administration, as is well known to those skilled in the art.

The compositions contain from about 5 to about 50 active ingredients in each dosage form.
It is preferred to formulate the unit dosage form to contain 0 m9, more typically 25 to about 300 m9. The term "unit dose form" refers to physically discrete dosage units suitable as unit doses for human subjects and other mammals,
Refers to a pharmaceutical form containing a precalculated amount of active ingredient and the desired pharmaceutical carrier in the hope that the desired therapeutic effect will be achieved.

Benzamide compounds are effective over a wide dose range. For example, the daily dose is usually lkl of body weight? It is about 0.5 to about 20 m9 per area. For adult treatment,
It is preferable to administer about 1 to 5 doses at once or in divided doses. However, the actual amount of compound administered will depend on the condition being treated, the route of administration chosen, the individual's age, body weight and response to treatment, and the severity of the patient's symptoms and the specifics chosen for administration. It is obvious that the benzamide compound etc. should be determined by a physician according to each situation.

[Examples] The method for producing the benzamide compound of the present invention and the formulation examples used will be described in more detail with reference to Examples below. These examples are for illustrative purposes only and the scope of the invention is not limited thereby.

(General matters) The melting point is determined by the Thomas-Hoov
er) The melting point was measured in an open glass tube using a melting point meter.

IR spectra were measured using a Veracts 24320 spectrophotometer using the sodium chloride cell method in chloroform solution or the fluorocarbon admixture method. 'I-I
NMR was performed using a Parian T-60A spectrometer, and all CD
Tetramethylnorane was used as an internal standard. Elemental analyzes (C, H, N) were performed at Atlantic Microlabs (Atlanta).

3- or 4-Nitrobenzanilide A solution of a suitable alkylaniline (0.03-0.07M) in 35 mQ of tetrahydrofuran was heated in a 20% aqueous potassium carbonate solution ( w/v) 2
00 M (l) was added to a three-neck flask containing excess 3- or 4-nitrobenzoyl chloride (2 times the mole).
A solution of 35x (l) of tetrahydrofuran was added dropwise thereto and the mixture was refluxed for 12 hours, keeping the p of the mixture at or above 8 during the reaction time. Then,
The solution was cooled to room temperature and extracted with chloroform (3x100+I2). The extracts were combined, dried over magnesium sulphate and the solvent was evaporated. The resulting residue was purified by recrystallization from a mixture of petroleum ether and benzene.

3- or 4-aminobenzanilides Pearl (Paa
To the hydrogenation bottle of r) was added a solution of a suitable 3- or nitrobenzanilide 5.09 in tetrahydrofuran or absolute ethanol and 5% palladium on carbon 25 (Lv 9). The mixture was subjected to low pressure hydrogenation (45 psi) for 3 hours. The contents of the bottle were filtered through Celite. The filtrate was evaporated and the resulting residue was recrystallized from a benzene/petroleum ether mixture or purified using petroleum ether (boiling point 30-60°C) and diethyl ether as solvents. , purified by silica gel (40 mesh) column chromatography using a stepwise gradient.

Example 1 4-Amino-N-(2,6-dimethylphenyl)benzamide A, Preparation of 4-nitro-N(2,6-dimethylphenyl)benzamide 2.6-dimethylaniline 0.09 mole tetrahydrofuran 35 mQ of solution was added to the IL flask for 20
% calcium carbonate aqueous solution (w/v) to a solution of 200 mQ. A solution of p-nitrobenzoyl chloride 209 in 35 mQ of tetrahydrofuran was added dropwise thereto. The resulting mixture was heated under reflux for 12 hours while maintaining the pr-t of 8 or more. Cool the solution to room temperature and
The mixture was then extracted three times with I 00 mQ of chloroform. The extracts were combined, dried over magnesium sulphate, and evaporated under reduced pressure. Crystallization of the resulting residue from petroleum ether/benzene yielded 15 g of the desired substituted intermediate. mp192-194°C.

8. Preparation of 4-amino-N-(2,6-dimethylphenyl)benzamide In a Parr hydrogenation bottle, add 1-nitro-N-(2,6
A solution of 5.0 g of -dimethylphenyl)benzamide in ethanol 250zQ was added along with 5% palladium on carbon 250zQ. The mixture was subjected to low pressure hydrogenation (45 psi) for 3 hours.
X bond/(inch)2). The mixture was filtered through Celite and the filtrate was evaporated under reduced pressure.

The resulting residue was purified by crystallization from petroleum ether/benzene or by silica gel column chromatography using a stepwise gradient of petroleum ether and diethyl ether as solvents to give the desired title compound 22.
I got a 9. mp212-2156C0 2C15H+eN Calculated value for 20: C174,97,H,6,7+,N,l I.

Actual measurements: C, 74,77, H, 6,75, N, +1°60° Examples 2 to 13 A series of 12 4
-An aminobenzanilide compound was created. Intermediate 4
-Nitrobenzanilides were prepared from 4-nitrobenzoyl chloride and a suitable alkylaniline by Schotten-Baumann type reaction conditions. Regarding them, please refer to the Ginturf [
(Sontag.

N, O, V,), Chemical Review (Chew, R
ev), Vol. 52, p. 237 (1953)]. The obtained 4-nitrobenzanilides are
Approximately 1670 CM-' by infrared absorption spectrum analysis
There was a crystalline solid in which carbonyl absorption was observed.

The aromatic nitro group was reduced by low pressure catalytic hydrogenation. The physical properties of the obtained 4-aminobenzanilides are shown in Table 1 together with the compound of Example 1.

The results of the initial evaluation of the anticonvulsant and toxic effects of the 1-aminohenzanilide compound of Example 1-13 are shown in Table 1 below. The test compound was administered to mice (intraperitoneal administration) at 30~G OOwg/kg to determine the effects on antimaximal electrostimulation seizures (MES) and convulsions produced by subcutaneous injection of metrazole (scMET), and neurology by rotary rod test. A preliminary evaluation was conducted to evaluate the lack of objectives. The intermediate 4-nitrobenzanilides were virtually ineffective in this anticonvulsant test.

Previously, Clark et al. showed that high anticonvulsant activity can be obtained by substituting the amino group nitrogen of the aromatic and arylalkyl groups of 4-aminobenzamides [Journal of Menocinal Chemistry (J, Med, Chem, ), vol. 27,
779 pages (1984) Ko.

As a result of such studies, the compound of Example 2 was 50mg/
A dose range of 9 was found to have activity against convulsions induced by MES and scMet. Table m shows the anticonvulsant effect when the aromatic ring is further substituted with an alkyl group. Example 1~
Thirteen compounds showed activity against MES-induced convulsions 30 minutes after dosing at 300 m9/9, and most compounds maintained at least minimal anti-MES activity up to 4 hours after dosing. For some compounds, s
It showed activity against convulsions induced by cMet, but the activity virtually disappeared after 4 hours. The monomethylanilides of Examples 3 to 5 are compound 2
showed similar anticonvulsant effects. Only compound 4 showed some appreciable difference between the toxicity and anti-ME, S effect produced by the dose m.

The compounds of Examples 6.7.8.119 and 10 are
All possible dimethylated anilide compounds, which show good anti-MES activity, compound 6 and compound l
was effective at 30yn/kei.

Compound 6 showed anti-MES activity in approximately half of the test animals when administered at 30 m97 to 9. Compound 1 showed high levels of anticonvulsant activity in the initial evaluation stage. The compound of Example 1 was administered at 3ou/k 30 minutes after administration.
All test animals treated with fI showed anti-MES activity and toxicity by rotary rod test.

Four hours after administration, the compound of Example 1 still showed sustained anti-MES activity at 30y and 97kg, but rotor toxicity had decreased to 9 at 100 m9/. No anti-scMet activity was observed after 30 minutes or 4 hours.

Compound l was further added at 5.10, 20 and 30 mgl
For each dose of kg, four test animals were used in each group, and a rotating rod test and an MES test were performed 30 minutes after administration. Rotary rod toxicity was observed in 3 out of 4 mice in the 20 sites/kg administration group, and anti-MES activity was observed in all 4 mice in the 5m9/kg administration group. From the results of initial testing of the compound of Example 1, its anticonvulsant activity spectrum is characterized as having significant activity in modifying maximal electric shock seizures, while having no activity against metrazole convulsions.

The remaining three compounds, Compounds 11 to 13, all had an isopropyl group in the ortho position and showed different activity-toxicity patterns. Compounds I2 and 13 showed excellent anti-MES activity, which appeared to be more potent than compound 11. However, compounds 11 and 12 showed similar toxicity patterns in this initial study. Compound 12 is 600 m
In contrast, compound 13 did not produce any rotor rod toxicity in the mice treated with 9/kfl.
Toxicity developed in 1 out of 4 treated animals. In the animals administered Compound 13, loss of righting reflex was observed in all 9 administration groups (1 out of 4 animals) at 300 vr, 9/9. This stark difference in the toxicity of compounds 12 and 13 is due to
This was truly unexpected considering the structural similarities of these two compounds.

Based on the results of the initial screening test, several 4-aminobenzanilide compounds were selected and quantitatively examined for their anticonvulsant effects and toxicity. The results of the evaluation are shown in Table 2 below.

In the test results reported in Table 1, E D s o values were determined for convulsions produced by MES and scMet, and TD5. The values were determined by the rotating rod method. Quantitative results were obtained for all compounds tested with respect to convulsions produced by MES, but the EDs o for scMet was slightly lower than that of Examples 2.4 and 9.
It was only possible to obtain this compound.

Compound 9 is the only compound with a higher PI value (PI-TD5°/ED5°) than compound 2 in anti-scMet activity. For these three compounds, the slopes (m) of the dose-response regression lines drawn for each compound all showed rather low values, indicating that the anti-scMet effect had extremely low selectivity. For example, compound 9 is anti-ME
For S, m=+2.0, whereas for anti-scMet, m=3.02.

Comparison of the anti-MESE D ao value and TD5° value in Table 2 shows that the compound of Example 4, which is a meta-toluinone derivative, is similar to the compound of Example 2, which is the current compound aniline derivative. It can be seen that it shows an activity spectrum. As discussed above, the compound of Example 1 showed significant levels of anti-MES activity in the initial anticonvulsant activity screening test.

By continuing to test lower dose levels, the anti-MESEDso of the compound of Example 1 was 2;
6 m9/9, T E 50 is 15.01 mg/9
I was able to confirm that. In addition, the compound of Example 1 is also compound 14, which was confirmed to have excellent anti-MES activity by Clark et al.
Chem, ), Vol. 27, p. 779 (1984)]. Compound 14 had a TD50 of 70.78 mg/9 by intraperitoneal administration in mice.
, anti-MES ED5. = 9 is shown in 18.02m9/. Therefore, the compound of Example 1 has 10 higher toxicity and anti-MES activity in mice than Compound 14.
It appears that it has doubled. However, compound 14 has anti-s
It has cMet activity (ED5Q=41.78i9/9), and the compound of Example 1 does not have this effect. Compound 14
The structure of is shown below.

The ortho-inopropyl derivatives in this invention (compounds of Example 11 and Example 12) exhibited the highest PlrX of the compounds tested in this study.

This Pl value is comparable to the much higher anti-MES ED5o value. The reason for the high PI values of these two compounds is that they have a particularly high FD. It can be said that it depends on the value (especially in compound I2). Toxicity evaluation of compound 12 1] 11 has r; and its 'I'D5o value is 1.
500~2000.7! // It was between ky. The significant increase in toxicity observed between Compound I2 and Compound 13, in which the substitution at the 6-position of the anilino ring was changed from methyl to ethyl, was unexpected for L5.

Determining the anticonvulsant activity of 4-aminohenozanilito compounds
From Table 1, it is possible to compare the anticonvulsant activity of these compounds (in particular Compound 1) with that of the anticonvulsants phenobalchtal, phenytoin and palproic acid. These drugs were tested using the same assay method. From the results, compound 1
shows higher potency than any of the basic anticonvulsant drugs,
Moreover, it was found that the PI values showed similar values. In many cases, the slopes of the regression lines for toxicity and activity are not necessarily parallel, and the PI value is only 50%
Determined by response dose. Therefore, the safety ratio of these compounds is 511
=TD3/ED9□), it is important to pay attention to the gradient effect. In the MES test, phenobarbicur (Sr (=2.3), phenytoin (SR=
3.6) and palproic acid (SR=0.9), the SR value of compound 1 was 1.6. Compound 14, which was compared in the same anti-MES test, had a 5R=3.5. The peak time of the onset of toxicity and anti-MES activity effects of Compound 1 was 30 minutes.

Compound! To investigate the general toxicity of r'Jj, its TD5o, 2XTD50 and 4XTDso doses were administered intraperitoneally to mice. Signs of toxicity developed at TDso doses are characterized by decreased motor activity, convulsive state, ataxia,
Toxicity manifested in the rotary bar test, and sedation. All these signs disappeared after 2 hours and the animals returned to normal appearance. Higher doses produced muscle relaxation, loss of righting reflex, decreased cyanotic respiratory rate, and ptosis in addition to these symptoms. Animals returned to normal appearance after 8 hours. Compound l ((I: drowsiness effect amount (IN
),. ) and lethal ff1(t, D50) were 43.80 m9/9 and 160, 83, respectively.
It was 9 in m9/. These values correspond to the corresponding phenobarbital (135, 45 and 264, 70 wg
/ 9), phenytoin (17834 and 22, 9)
61 rH/9), palproic acid (885,53 and +104.62 rH/9) and compound +4 (461,
76 and 718.18z9/ni9) from Ia α1 (Mr.

The anticonvulsant activity spectrum of Compound 1 was investigated using convulsions induced in mice by a series of chemical substances. Compound I is 30 mg7k for convulsions caused by metrazole (subcutaneous), bicuculline (subcutaneous), bicrotoxin (subcutaneous) and strychnine (intramuscular).
It was invalid in usage types up to g. Bicuculline and picrotoxin cause convulsions through GABA antagonism [Krogesgaard-Larsen, Journal of Med, Chem.
), vol. 24, p. 1377 (1981)], strychnine blocks the postinhibitory inhibition conveyed by glycine [Fral et al., Epilepsia
a)]. Compound 1 is thus ineffective in all chemical threshold tests and therefore exhibits a spectrum of activity similar to phenytoin.

(Pharmacological test example) Initial evaluation of anticonvulsant activity of compounds 1-13 was conducted at at least 3 dose levels (30, 100, 300, x9/&y)
In some cases, one more stage (600m
9) was added to 9/. Test animals were all male Carworth Farms Number One mice (Carworth Farms Number One Mouse).
worth Farms number-one
m.

use) was used. All compound test solutions were prepared at 30% in polyethylene glycol 400 and administered intraperitoneally (ip) to the animals for 300 minutes of testing.

Maximal electrostimulation seizures (MES) were elicited by applying 60 cycles of alternating current at 50 mA intensity through a corneal electrode. One drop of 0.95 saline solution was placed in the eye before electrode attachment. This was measured and evaluated by the occurrence of clonic, flexor-tonic or extension-tonic convulsions, or death in the animal immediately after electrical stimulation. The shedding of the tonic extensor component of the seizure seen in the hind limbs is defined as the manifestation of a defensive response in the MES test. Immediately after electrical stimulation, the dose capable of suppressing the induction of tonic convulsions in the hind limbs in half of the animals was determined by graphical interpolation, and the ED5° of the test compound was thereby determined.

Bentetrazole (metrazole) subcutaneous convulsion threshold testing (scMet) was performed by administering bentetrazole in a 0.5% solution from the posterior midline at 85Il18/9. In this test, a protective response was defined as the absence of one episode of clonic convulsion lasting at least 5 seconds during observation for 30 minutes after administration of the test compound.

Neurological deficits were measured using the rotating rod test in mice. Animals treated with test compound are mounted on a 1 inch (approximately 2.54 cm) diameter notched plastic rod rotating at a speed of 6 rpm. Neurotoxicity was defined when the animal was unable to stay on the rod for 1 minute. Median anticonvulsant potency (ED50) and median toxicity (TD5o) were determined by graphical methods.

In the examples below, the compound of Example 1, 4-amino-N-(2,6-nomethylphenyl)benzanilide, is shown as a preferred anticonvulsant in the form of various pharmaceutical compositions that can be used as a preferred anticonvulsant. The use of this invention as a medicine will be explained.

Example 15 A gelatin hard capsule is prepared from the following ingredients Content (m9/capsule) 4-Amino-N-(2,6-dimethylphenyl)benzamide sulfate 250 dry starch 200 Magnenium stearate IO Mix the above ingredients. , content ff14
Fill 60 m9 into hard gelatin capsules.

Example 16 Prepare tablets from the ingredients listed below.

Content (g peel/tablet) 4-Amino-N-(2,6-nomethylphenyl)benzamide hydrobromide 250 Microcrystalline cellulose 400 Melted silicon dioxide IO stearic acid
5. Mix the above ingredients and press into 665Q tablets.

Example 17 Prepare an aerosol solution containing the following ingredients:

Weight (%) 4-Amino-N-(2,6-dimethylphenyl)benzamide hydrochloride 0.25 Ethanol 29.75 Propellant 22 (dichlorofluoromethane) 70. Q O
The active compound is mixed with ethanol, this mixture is added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. Pour the desired amount into a stainless steel container,
Dilute with the remainder of Propellant 22. Next, attach the Harb set to the container.

Example 18 Tablets containing active ingredient 6018 are prepared as follows.

Content (7g) 4-Amino-N-(2,6-nomethylphenyl)benzamide 60 Ten 45 Fine cellulose 35 Polyvinylpyrrolidone (!
0% aqueous solution) 4 Sodium carboxymethyl starch 4.5 Magnenium stearate 0.5 Talc
Total amount: 150 Pass the active ingredient, starch and cellulose through a No. 45 Metsuyu U, S sieve (US standard sieve) and mix thoroughly. The obtained powder was mixed with a polyvinylpyrrolidone aqueous solution, and mixed with a No. 14 mesh U.

S. Pass through a sieve. The granules prepared in this way are
Dry at 60°C and use No. 18 mesh U and S.

Pass through a sieve. To the granules, sodium carboxymethyl starch, magnesium stearate, and talc, which have been passed through a No. 60 mesh US sieve, are added, mixed, and then pressed using a key press to form tablets weighing 15 (L+g) each.

Example 19 Capsules containing drug 80 are prepared as follows.

Content (mg) 4-Amino-N-(2,6-dimethylphenyl)benzamide 80 Starch 59 Micrograde cellulose 59 Magnenium stearate 2 Total amount 200 The active ingredients, cellulose, starch and magnesium stearate were mixed and mixed into a No. 45 mesh Pass through U and S sieves and fill into hard gelatin capsules with a content of 200 mg.

Example 20 A crude drug containing the active ingredient 225π9 was prepared as follows!
A sell.

Content (mg) 4-Amino-N(2,6-medylphenyl)benzamide 225 Saturated fatty acid 2000 Active ingredients 6
Pass through No. 0 mesh U and S sieves, and suspend in saturated fatty acids that have been pre-melted by applying minimal heat. Next, this mixture is poured into a herbal medicine mold with a nominal weight of 2 g and left to cool.

Example 21 A suspension containing 50 m9 of drug in 5 doses is prepared as follows.

Content 4-amino-N-(2,6-nomethylphenyl)benzamide hydrochloride 50ffl) Sodium carboquine methylcellulose 50mg syrup 1.25. +y12 benzoic acid solution 0.10 inch flavor Appropriate amount coloring agent
Add an appropriate amount of purified water to make a total of 15m12.

The drug is passed through a No. 45 mesh U, S, sieve and mixed with carboxymethyl cellulose sodium and Nlop to form a uniform paste.

The benzoic acid solution, flavor and color are diluted in a small amount of water and added without stirring. Then add an appropriate amount of water to adjust to the desired volume.

Example 22 Similarly, a 3-amino compound of this invention was prepared and evaluated as an anticonvulsant. This compound is 3-amino-N-(
2,6-dimedylphenyl)benzamide, shown as compound n-t in Table 1 above. This compound was prepared according to Scheme I above, starting from 3-di)-lobenzoyl chloride and 2,6-nomethylaniline, under the experimental conditions described below in the General section.

The melting point of 3-amino-N-(2,6-nomethylphenyl)benzamide is 200-200°C, and the rR wavenumber is 166.
It was 5.1620 cm-'. In addition, the experimental formula C1sH
+eNtO+l: Calculated value: C17497%, H, 6,71%, N1116
6% Actual value: C, 74,87%, H, 6,73%, N111
It was 63%.

The T D s of this compound was evaluated for anticonvulsant activity in male Carworth Farms Number One mice by the method outlined in the Pharmacology Testing Examples section. value is 2
84.57mg/9, MES ED50 value is 3
, 48 H/kg, MES PI value is 2111 ε
The term "benzanilide" as used in connection with the compounds of this invention refers to an unsubstituted compound having the structure shown below.

The compounds of this invention are also referred to as benzamides of anilines and unsubstituted anilines.

All study results reported herein are sponsored by the Anticompulsant Drug Tuberobement Program, the Elevacy Branch, the Neurological Disorders Program, and the National Institute of Neurological and Communicative Research. Disorders and Strokes (Anti
conv-ulsantDrug Develop
ent Program, EpilepsyBr
anch, Neurological Disord
ers Program.

National Intitude of
Neurological and Communica
tive D 1sorders and S tr
oke). The test method used was the experimental evaluation method described by Reinhard and Reinhard Jr. in Anticonvulsants J, edited by Vida, Academic Press, New York. Of Anticompulsants (Experim)
mental Evaluation of An
(1977).

Further, many test methods are described in US Pat. No. 4,379,165, and some of the terms used in the activity test of this invention are also related thereto. In this regard, a portion of this US Pat. No. 4,379,165 is cited.

The 3- and 4-amino-N-(alkylphenyl)benzamide compounds presented in this invention, Tokuni-amino-N-(2,6-dimethylphenyl)benzamide, have a high therapeutic index and a long half-life. It is an anticonvulsant drug and is therefore useful in the treatment and prevention of convulsions in mammals. In particular, these compounds are effective against tonic-extensor seizures elicited by maximal electrical stimulation; therefore, these compounds are effective against whole-boiled tonic-clonic seizures (“grand mal”), corticofocal seizures, and complex seizures in humans. Useful in the treatment of partial-onset seizures (temporal lobe epilepsy), simple partial-onset seizures (focal motor seizures), and post-traumatic seizures. This activity was demonstrated by the convulsive inhibition test elicited by maximal electrical stimulation as disclosed herein.

Claims (19)

[Claims] (1) 3- or 4-amino-N- per unit dose
[(alkyl)nphenyl]benzamide, where the alkyl group contains 1 to about 4 carbon atoms, and n is 1 or 2
or about 5 to about 500 mg of a pharmaceutically effective acid addition salt thereof.
A pharmaceutical composition useful for the treatment or prevention of convulsions in a mammal in unit dosage form, comprising a pharmaceutically acceptable carrier, diluent, or excipient. (2) The above benzamide has the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R is C_1 to C_4 alkyl, n is 1 or 2
The composition according to claim 1, which is a 3- or 4-amino-N-benzanilide having a structure represented by thing. (3) The composition according to claim 1 or 2, wherein the benzamide is 3-amino-N-benzamide. (4) The composition according to claim 1 or 2, wherein the benzamide is 4-amino-N-benzamide. (5) Claim 4, wherein the benzamide is 4-amino-N-(2,6-dimethylphenyl)benzamide.
Compositions as described in Section. (6) The benzamide is at least the following: 3-amino-N-(2,6-dimethylphenyl)benzamide, 4-amino-N-(3-methylphenyl)benzamide, 4-amino-N-(2,4- dimethylphenyl)benzamide, 4-amino-N-(3,4-dimethylphenyl)benzamide, 4-amino-N-(3,5-dimethylphenyl)benzamide 4-amino-N-(2-isopropyl-6-methyl phenyl)benzamide, 4-amino-N-(2-isopropylphenyl)benzamide, 4-amino-N-(2-isopropyl-6-methylphenyl)benzamide, 4-amino-N-(2-isopropyl-6-ethyl phenyl)benzamide, 4-amino-N-(2-methylphenyl)benzamide, or 4-amino-N-(4-methylphenyl)benzamide according to claim 1 or 2. Composition. (7) 3- or 4-aminobenzanilide having a structure represented by the following formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, each substituent is in the following position: ). (8) 3-amino-N-(2,6-dimethylphenyl)
The compound according to claim 7, which is a benzamide. (9) The compound according to claim 7, which is 4-amino-N-(3-methylphenyl)benzamide. (10) The compound according to claim 7, which is 4-amino-N-(2,4-dimethylphenyl)benzamide. (11) The compound according to claim 7, which is 4-amino-N-(3,4-dimethylphenyl)benzamide. (12) The compound according to claim 7, which is 4-amino-N-(3,5-dimethylphenyl)benzamide. (13) Claim 7 which is 4-amino-N-(2-isopropyl-6-methylphenyl)benzamide
Compounds described in Section. (14) The compound according to claim 7, which is 4-amino-N-(2-isopropylphenyl)benzamide. (15) Claim 7 which is 4-amino-N-(2-isopropyl-6-methylphenyl)benzamide
Compounds described in Section. (16) Claim 7 which is 4-amino-N-(2-isopropyl-6-ethylphenyl)benzamide
Compounds described in Section. (17) The compound according to claim 7, which is 4-amino-N-(2-methylphenyl)benzamide. (18) The compound according to claim 7, which is 4-amino-N-(4-methylphenyl)benzamide. (19) The compound according to claim 7, which is 4-amino-N-(2,6-dimethylphenyl)benzamide.